Supported phase catalyst

ABSTRACT

Supported phase catalysts in which the support phase is highly polar, most preferably ethylene glycol or glycerol, are disclosed. An organometallic compound, preferably a metal complex of chiral sulfonated 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl is dissolved in the support phase. Such supported phase catalysts are useful for asymmetric synthesis of optically active compounds, including the asymmetric hydrogenation of prochiral unsaturated carbon-hetero atom bonds, such as ketones, imines and beta-keto esters.

REFERENCE TO RELATED APPLICATIONS

This is a divisional of application Ser. No. 08/838,730, filed Apr. 10,1997 now U.S. Pat. No. 5,935,892 which is a continuation-in-part ofpending U.S. application Ser. No. 08/371,880 filed Jan. 12, 1995 nowU.S. Pat. No. 5,736,480, which is a continuation-in-part of pending U.S.application Ser. No. 08/199,086 filed Feb. 22, 1994, now abandoned whichapplications are incorporated herein by reference.

The U.S. Government has certain rights in this invention pursuant toGrant No. CTS-9021017 awarded by the National Science Foundation.

TECHNICAL FIELD

The present invention is directed to supported phase catalyst systems inwhich an organometallic catalyst is solubilized in the supported phase,and the use of such catalysts in asymmetric hydrogenation reactions.

BACKGROUND OF THE INVENTION

The development of effective asymmetric reactions that enable theenantioselective formation of one chiral center over another continuesto be an important area of research. One such asymmetric reactioninvolves the introduction of a chiral center into a molecule through theenantioselective hydrogenation of a prochiral unsaturated bond by usinga transition metal catalyst bearing chiral organic ligands. Numerouschiral phosphine catalysts have been developed to enantioselectivelyintroduce chiral centers to prochiral olefins, carbonyls and imines withhigh enantiomeric excess. One such class of chiral catalysts employs thechiral phosphine ligand 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(hereinafter referred to as “BINAP”).

A second important area of research relates to the development ofwater-soluble organometallic catalysts. Conventionally, catalyticallyactive organometallic complexes have been applied as homogeneouscatalysts in solution in the organic reaction phase. Difficultiesassociated with recovery of the homogeneous catalysts from the reactantsand products diminish the utility of these homogeneous catalysts,especially when the cost of the catalyst is high or where there is theneed to isolate the reaction products in high purity.

One mode in which water soluble organometallic catalysts have been usedis in two phase systems comprising an aqueous phase and a waterimmiscible phase (e.g. ethyl acetate-water). Separation of theorganometallic catalyst from organic reactants and products is greatlysimplified due to the insolubility of the catalyst in the waterimmiscible phase. However, in some instances, the utility of the twophase system has been limited by a lack of substrate and/or reactantsolubility in the aqueous phase, by the limited interfacial area betweenthe two phases, and by poor selectivity.

Supported phase (SP) organometallic catalysts have been developed toovercome some of the shortcomings associated with two phase reactionsystems. In a supported phase system the interfacial area between thesupport phase, which contains the organometallic catalyst, and the waterimmiscible (bulk organic) phase, is greatly enhanced.

The advantages of supported phase organometallic catalyst systems haveprompted further investigation into catalyst systems which will retainthe beneficial characteristics thereof while further increasing yieldand enantioselectivity.

SUMMARY OF THE INVENTION

Such further advantages are achieved by the present invention, whichrelates to supported phase catalysts in which the support phase containsa highly polar and non-aqueous liquid, such as an alcohol with two ormore hydroxy groups, preferably glycerol, a triol.

In this regard, the present invention is a supported phase catalystsystem wherein glycerol forms the supported phase. An organometalliccompound, preferably a metal complex of chiral sulfonated2,2′-bis(diphenylphosphino)-1,1′-binaphthyl is dissolved in glycerol.While the use of a diol, such as ethylene glycol is within the scope ofthe invention, the use of glycerol in the solvent support phase in asupported phase catalyst system offers the further advantage of safetydue to the relatively low toxicity of glycerol as compared to ethyleneglycol.

The invention further includes the use of such supported phase catalystsfor asymmetric synthesis of optically active compounds containing chiralcarbon-carbon and carbon-hetero atom bonds, such as the preparation ofdehydronaproxen, or the asymmetric hydrogenation of ketones, imines, orbeta-keto esters, such as ethyl butyrylacetate. Generally, suchasymmetric reactions include those reactions in which organometalliccatalysts are commonly used, such as reduction and isomerizationreactions on unsaturated substrates and carbon-carbon bond formingreactions, and specifically hydrogenation, hydroboration,hydrosilylation, hydride reduction, hydroformylation, alkylation,allylic alkylation, arylation, alkenylation, epoxidation,hydrocyanation, disilylation, cyclization and isomerization reactions.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be better understood by reference to the appendedFIGS. 1A-1C which are diagrams of the preferred catalyst system of theinvention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The present invention relates to an improved supported phase catalystsystem, and its use in asymmetric synthesis of optically activecompounds containing carbon-carbon or carbon-hetero atom bonds.

One advantage of supported phase (SP) catalysts is the simplicity ofcatalyst recovery. When a SP catalyst is used in an organic solvent, theorganometallic catalyst is retained within the supported solutionimmobilized on the surface of a solid support (catalyst particle) andthus can be easily recovered by simple filtration.

With respect to the catalysts useful in the present invention, chiralsulfonated 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP-SO₃Na)ligands in the form of organometallic catalysts are preferred.

It is most preferred that the chiral sulfonated BINAP be tetrasulfonated(BINAP-4SO₃Na). Metals used to form such catalysts include, but are notlimited to, rhodium, ruthenium, iridium, vanadium, lead, platinum, tin,nickel or palladium. With regard to hydrogenation reactions, rutheniumis the most preferred metal. It is also preferred that the catalystcomprise counterions, most preferably Na⁺, K⁺, Cs⁺ and Ca²⁺. Thepreferred sulfonated BINAP catalyst, [Ru(benzene)(Cl)(BINAP-4SO₃Na)]Cl,is structured as follows:

Asymmetric reactions for which the SP catalysts of the invention can beused include those reactions in which organometallic catalysts arecommonly used. Such reactions include reduction and isomerizationreactions on unsaturated substrates and carbon-carbon bond formingreactions, such as hydrogenation, hydroboration, hydrosilylation,hydride reduction, hydroformylation, alkylation, allylic alkylation,arylation, alkenylation, epoxidation, hydrocyanation, disylylation,cyclization and isomerization reactions. In these reactions, a catalystis generally used to catalyze the enantioselective transformation of aprochiral unsaturated substrate. Types of prochiral unsaturatedsubstrates asymmetrically reacted using the sulfonated BINAP catalystsinclude alkenes, aldehydes, ketones, thioketones, oximes, imines,enamines, allylic alcohols, allylamines, unsaturated carboxylic acidsand others.

The sulfonated catalysts useful in the present invention are soluble inhighly polar solvents such as alcohols with two or more hydroxy groups,for example, ethylene glycol or glycerol. The sulfonated catalysts arenot soluble in nonpolar solvents such as hexane. As a result, thecatalysts of the present invention may be employed in such alcoholswhere the alcohol is contained in or as the immobilized solvent on thesurface of a solvent/catalyst support particle.

In each case, the sulfonated catalysts used in the invention aresolvated by the supported phase and thus are available to catalyze thedesired asymmetric reactions.

EXPERIMENTAL

Ruthenium based sulfonated BINAP catalysts are preferred because theyexhibit higher stability, superior enantioselectivity, and catalyze awider range of reactions than, for example, corresponding rhodium basedsulfonated BINAP catalysts.

The following examples set forth the synthesis of chiral sulfonatedBINAP catalysts and their use in a SP catalytic system. It is understoodthat reactions relating to either the (R)- or (S)-BINAP catalyst can beequally employed using the other enantiomer. Therefore, specificrecitation to (R)- or (S)-BINAP, or derivatives thereof, are notintended to be limiting.

As used herein, an enantioselective reaction is one where oneenantiotopic face is selectively attacked over the other thereby causingthe formation of one enantiomer over another. Enantiomeric excess (e.e.)is a measurement of a reaction's enantioselectivity and is defined bythe quantity$\frac{\left( {R - S} \right)}{\left( {R + S} \right)} \times 100\%$

where R and S are relative quantities of R and S enantiomers.

EXAMPLES

1. Sulfonation Of (R)-BINAP

Sulfonation of (R)-BINAP was carried out under conditions designed tominimize the formation of phosphine oxides and to selectively producethe tetra-sulfonated BINAP derivative. First, 1 g of (R)-BINAP wasdissolved in 3.5 ml of concentrated sulfuric acid at 10° C. under argon.Afterward, 15 ml of fuming sulfuric acid (40 wt % sulfur trioxide inconcentrated sulfuric acid) was added dropwise over 2-3 hours. Theresulting solution was then stirred at 10° C. under an argon atmospherefor 3 days. In the event that the reaction mixture solidifies, it ispreferred that a stepwise addition of sulfur trioxide be used ratherthan a dropwise addition in order to prevent solidification.

After stirring, the reaction was quenched by pouring the sulfuric acidsolution into 100 ml of ice cooled water followed by the dropwiseaddition of 50 wt % NaOH until the solution was neutralized to pH 7. Theresulting aqueous solution was then reduced to 30 ml under vacuum. 100ml of methanol was then added to the concentrated solution in order toprecipitate any sodium sulfate present in solution. The sodium sulfatewas removed by filtration and the supernatant reduced under vacuum toyield a solid. The solid was then dissolved in neat methanol to removetrace amounts of sodium sulfate to yield sulfonated (R)-BINAP in a70-75% yield.

Our earlier U.S. application Ser. No. 08/371,880 describes thecharacterization of the resultant sulfonated (R)-BINAP derivatives.Tetrasulfonated BINAP, which was monosulfonated on each phenyl ring, wasformed at 85%. Minor products of the reaction include higher sulfonatedBINAP derivatives, such as penta- and hexa-sulfonated BINAP derivatives,which are also effective as enantioselective catalysts.

2. Preparation Of Ruthenium BINAP-4 SO₃Na Catalyst

Ruthenium BINAP-4 SO₃Na catalyst was prepared by reacting[Ru(benzene)Cl₂]₂ with two equivalents of (R)-BINAP-4SO₃Na in a 1:8benzene/methanol solvent to yield [Ru(benzene)Cl[(R)-BINAP-4 SO₃Na]]Cl.³¹P NMR (CD₃OD): d.d. δ=63.0, δ 68.8 ppm J=45 Hz. Specifically, 0.0010 gof [Ru(benzene)Cl₂]₂ was stirred with 0.0050 g BINAP-SO₃Na in 4.5 ml ofa 1:8 benzene/methanol solvent at 55° C. under argon for 1-2 hours. Theresulting solution was then vacuum dried at room temperature (“dried”catalyst).

3. Asymmetric Hydrogenation Using Ethylene Glycol As The Supported Phase

The organometallic ruthenium catalyst of Example 2 exhibits a solventdependent enantioselectivity when operated homogeneously. Although thishomogeneous organometallic ruthenium catalyst is effective in promotingthe asymmetric hydrogenation of 2-(6′-methoxy-2′-naphthyl)acrylic acid(substrate 1) with 96% e.e. in neat methanol, the enantioselectivitydrops to about 80% e.e. in water. As a result, the enantioselectivity ofthe catalyst when supported in an aqueous phase, i.e., a hydratedsupported aqueous phase (SAP) catalyst, is bounded by the intrinsicenantioselectivity limit of the organometallic ruthenium complex in neatwater. Hence, further refinements on the SAP catalyst are made, enablingthe development of a practical, general-use, heterogeneous, chiralcatalyst.

In this example, we describe the detailed design and synthesis ofanother new heterogeneous catalyst and its use in the asymmetrichydrogenation of 2-(6′-methoxy-2′-naphthyl)acrylic acid to naproxen. Wefurther describe the composition of this new catalyst, a new method forthe activation of the “dried” catalyst, and reaction conditions thatprevent leaching.

The catalyst system of this example is shown in FIGS. 1A-1C. FIGS. 1A-1Cshow the use of ethylene glycol and/or glycerol as the support phase foran organometallic catalyst such as sulfonated BINAP.

The materials used in this example are as follows: controlled pore glassCPG-240 (a narrow pore-size distribution glass: mean pore diameter=242Å, pore volume=0.89 ml/g, surface area=79 m²/g, mesh size=120/200),benzeneruthenium (II) chloride dimer, ethyl acetate, cyclohexane,chloroform, ethylene glycol and triethylamine in their highest purityavailable. Unless otherwise noted, the sodium salt of tetra-sulfonatedBINAP is prepared as above (Example 1) and all manipulations areperformed under argon or nitrogen. Deionized water, distilled overpotassium permanganate are used in all operations requiring water. Allsolvents, including water, are degassed by four to five freeze-pump-thawcycles.

The catalyst is prepared and activated in the following manner. Theactive organometallic ruthenium catalyst,[Ru(BINAP-4SO₃Na)(benzene)Cl]Cl, is prepared and impregnated onto theCPG support. The water content of this “dried” catalyst is estimated bythermogravimetric analysis to be 1.9 wt %, while the ruthenium contentswere 1.2-2.5×10⁻⁵ mol/g and anhydrous ethylene glycol is used toactivate the “dried” catalyst. The activation of the catalyst isperformed by two different techniques: (A) by the in-situ activationwith ethylene glycol in ethyl acetate (ethylene glycol partitionsbetween the organic solvent and the surface of the CPG), and (B) asfollows. The “dried” catalyst is stirred in ethyl acetate that had beenpreviously premixed with a controlled amount of ethylene glycol. Thehighly polar ethylene glycol must be allowed to partition between theethyl acetate phase and the CPG surface for about one hour. Because of asmall partition coefficient for ethylene glycol between the CPG supportand the ethyl acetate, most of the ethylene glycol should remain in thebulk organic phase upon contact with the “dried” catalyst. Thisprocedure is then repeated. The bulk organic phase is removed byfiltration and the resulting catalyst is washed several times with a 1:1chloroform and cyclohexane mixture that had been pre-mixed with ethyleneglycol.

Asymmetric hydrogenations of 2-(6′-methoxy-2′-naphthyl) acrylic acid areconducted at various temperatures in a 25 ml stainless steel Parr batchreactor. Special care should be taken to avoid introducing oxygen intothe reaction mixture at all times. Both the neat ethyl acetate and the1:1 mixture of chloroform/cyclohexane may be used as the bulk organicphase (5 ml). The hydrogenation reaction is best measured by ¹H NMRspectroscopy and the enantiomeric excess (e.e.) determined by HPLC.

The asymmetric hydrogenation of 2-(6′-methoxy-2′-naphthyl)acrylic acid(substrate 1) is chosen to be our model reaction. Our work shows thatthe presence of water tends to lower the enantioselectivity in thehomogeneous hydrogenation of the substrate in methanolic solvents.Aquation of the ruthenium-chloro bond in water is, therefore responsiblefor this solvent dependent enantioselectivity. To prevent the cleavageof the ruthenium-chloro bond, anhydrous ethylene glycol is used here inplace of water. A ³¹P NMR spectrum of the ruthenium complex in 1:1CD₃OD/ethylene glycol reveals the same two doublets (δ=63.0 and 68.8ppm; J≈45 Hz) as are found in neat methanol indicating that theruthenium-chloro bond in [Ru(BINAP-4SO₃Na)(benzene)Cl]Cl is stillintact. Upon addition of water, only a singlet (δ=57.5 ppm) is observedin the ³¹P NMR spectrum. These data suggest that a rapid hydrolysis ofthe ruthenium-chloro bond has occurred in the presence of water. As aresult, hydrogenations of substrate 1 are carried out in the presence ofethylene glycol. Similar enantioselectivities (88-89%) are observed forreactions carried out in neat methanol, 1:1 methanol/ethylene glycol andalso in neat ethylene glycol. These findings further support the premisethat the cleavage of the ruthenium-chloro bond has a detrimental effecton enantioselectivity. An e.e. of only 79% is observed in a 1:1 MeOH/H₂Osolvent mixture. Thus, since the highly polar ethylene glycol is notmiscible with most organic solvents, it can be used as a substitute forthe aqueous phase in the SAP system; it replaces the role of water inthe immobilization of the ruthenium catalyst onto the CPG support.

This new heterogeneous catalyst now comprises or consists of a rutheniumorganometallic complex dissolved in a film of ethylene glycol which issupported on a high-surface-area hydrophilic (e.g. CPG) support (FIGS.1A-1C).

With the in-situ activation using ethylene glycol, enantioselectivitiesare found to increase with increasing amount of ethylene glycol in thesystem. The enantioselectivities as a function of ethylene glycolcontent are listed in Table 1 (reaction conditions:substrate/ruthenium=30, [substrate]=3.6×10⁻³ M, solvent volume=5 ml,pressure=1400 psig, T=24° C., stirring speed=350 rpm). At a maximumethylene glycol loading of 400 μl in 5 ml of ethyl acetate an 87.7% e.e.is observed, while only 45.0% e.e. is found for the system with 75 μl ofethylene glycol. These results are in agreement with our previousfindings for the hydrated SAP systems where the higher the water contentthe higher the enantioselectivity. More importantly, the newheterogeneous catalyst with ethylene glycol as a substitute for theaqueous phase achieves the same high enantioselectivity as itshomogeneous analogue in neat methanol. By lowering the reactiontemperature to 3° C., the e.e. is increased to 94.8%. However, unlikethe homogeneous analogue in neat methanol, addition of triethylamine tothe heterogeneous catalyst is found to have a detrimental effect onenantioselectivity. An almost 15% drop in e.e. is observed at roomtemperature upon addition of triethylamine. This is rather unexpectedsince we believe that the active ruthenium catalyst is nearly the sameas the one in neat methanol. Solvation of the ruthenium complex withethylene glycol may be responsible for the decline in enantioselectivityupon addition of base, but the detailed mechanism is still unclear. Asimilar drop in e.e. is also reported in our original hydrated SAPsystem.

For long-term stability, the heterogeneous catalyst must also remainassembled. To test for this type of stability, the followingself-assembly test is performed: 1.1×10⁻⁶ moles of[Ru(BINAP-4SO₃Na)(benzene)Cl]Cl is dissolved in 400 μl of ethyleneglycol and loaded into a 25 ml Parr reactor. 5.7×10⁻⁵ moles of substrate1 in 5 ml of ethyl acetate is then added. Finally, 0.1 g CPG-240 isadded. The reactor is pressurized to 1,400 psig with hydrogen andstirred at 350 rpm and at room temperature. The reaction is stoppedafter one hour and analyzed. A control experiment is carried out inusing exactly the same procedure with the exception that no CPG isadded. Complete conversion of substrate 1 is observed when CPG is added,while no detectable conversion is found in the control experiment. Afterthe reaction, the CPG support turns pale yellow and the bulk organicphase is colorless. These results indicate that, under the reactionconditions, the individual components of the heterogeneous catalystself-assemble into a more thermodynamically stable supported-catalystconfiguration. Therefore, the reverse, i.e., the separation of thesolution and complex from the support, is unlikely to occur underreaction conditions because such a separation is not thermodynamicallyfavored. These results also support the inference that the reactionchemistry is taking place at the liquid-liquid interface. In the controlexperiment, most of the added ethylene glycol dissolved into the bulkorganic phase and left behind small droplets of catalyst solution. Thelimited interfacial area of the catalyst solution that remainsimmiscible with the bulk organic phase results in the lack of activityin the control experiment.

Unlike a hydrated SAP catalyst, traces of ruthenium are found in thereaction filtrates. The extent of ruthenium leaching was found to becorrelated with the ethylene glycol content in the organic phase asevidenced by the data shown in Table 2. Since ethylene glycol is lesspolar than water, it is at least 3 times more soluble than water inethyl acetate. The higher solubility of ethylene glycol in ethyl acetateis likely responsible for the observed leaching of ruthenium into thebulk organic phase. In order to minimize the leaching of ruthenium intothe bulk organic phase, a new method of activation of the “dried”catalyst with ethylene glycol was devised, and is described below.

The “dried” catalyst is activated by stirring it in an ethyleneglycol/ethyl acetate solvent mixture. After equilibration for an hour atroom temperature, the solid catalyst is filtered and dried at low vacuum(0.2 atm.). The procedure is then repeated. Only a thin film ofnon-volatile ethylene glycol is deposited onto the solid catalyst. Theamount of ethylene glycol in the film is approximately the same as thatfound with the original in-situ activation procedure, and a similardegree of mobility of the ruthenium complex on the support is to beexpected. However, in this embodiment an ethylene glyco-saturatedorganic phase is used so as to maintain the integrity of this filmduring the reaction. To minimize the amount of ethylene glycol used inthe bulk organic phase, a 1:1 solvent mixture of cyclohexane andchloroform (for solubilization of substrate) is used. As shown in Table3, the same high enantioselectivity (88.4% e.e. at room temperature) isstill obtained with this kind of activation procedure and moreimportantly, no ruthenium is found in the reaction filtrate at adetection limit of 32 ppb. By lowering the reaction temperature to 3°C., an 95.7% e.e. is obtained with this new heterogeneous catalyst. Asshown in Table 3, the present system is already as enantioselective asits homogeneous analogue (95.7% vs. 96.1%). Thus, recycling of thecatalyst is possible without any loss in enantioselectivity.

Using the new formulation, another self-assembly test is again carriedout to verify the long-term stability of the catalyst. 1×10⁻⁷ moles ofthe ruthenium complex in 50 μl of ethylene glycol is mixed with 4×10⁻⁶moles of substrate in 5 ml of 1:1 chloroform/cyclohexane. 0.2 g ofCPG-240 are added, and then the reactor is pressurized to 1,400 psigwith hydrogen and the mixture is stirred at room temperature for 2hours. Complete conversion is observed. However, less than 2% conversionis found from the control experiment where no CPG was added. Theseresults again indicate that, under these new reaction conditions, theindividual components of the present catalytic system self-assemble intothe more stable supported-catalyst configuration.

With comparable activity and enantioselectivity to the homogeneouscatalyst, the present heterogeneous catalyst can be considered a genuinehybrid of homogeneous and heterogeneous catalysts. As compared to theasymmetric hydrogenation catalysts anchored in modified USY zeolites,Corma et al., J.C.S., Chem. Commun. 1253 (1991); Sanchez et al., J. Mol.Catal. 70, 369 (1991), this example of our invention has severaldistinguishing features. The CPG support possesses large and uniformpore diameters that allow large bio-substrate access to the catalyticsites. Also, CPG supports are commercially available in a wide range ofpore diameters (75-3000 Å); for the zeolite-supported catalyst, thesmall pore size (˜8 Å) limits the size of substrate. Furthermore, theactive rhodium complex is covalently bonded to the zeolite framework andreasonable activity can only be reached at elevated temperature (60°C.). In contrast, the active ruthenium complex in the present system isdissolved in ethylene glycol, which is immobilized as a thin film on theCPG support. At molecular level, this method of immobilization yields aheterogeneous catalyst that is basically the same as its homogeneousanalogue, thus allowing for the high enantioselectivity and activity.

TABLE 1 Enantioselectivities in the reduction of substrate as a functionof ethylene glycol content in organic phase† Ethylene Glycol content(μl) e.e. (%)  75 45.0 150 72.1 270 82.1 350 84.2 350 71.3^(a) 35091.1^(b) 400 87.7 400 94.8^(b) †catalysts were activated by in-situorganic-phase impregnation with 5 ml of ethyl acetate;substrate/ruthenium = 30; pressure = 1400 psig and at room temperature^(a)with addition of triethylamine ^(b)reaction temperature = 3° C.

TABLE 2 Ruthenium leaching as a function of ethylene glycol content inthe reduction of substrate* Ethylene Glycol content† (μl) Ruthenium‡(ppm) 150 0.17 270 0.27 350 0.23^(a) 400 0.37 *substrate/ruthenium = 30;H₂ pressure = 1350-1450 psig; reaction temp. = 24° C.; stirring speed =350 rpm †in-situ catalyst activation with method (A) ‡ruthenium contentin the reaction filtrates ^(a)reaction temperature = 3° C.

TABLE 3 Enantioselectivities in the reduction of substrate withruthenium catalysts in different configurations* Catalyst Solvent e.e.(%) Heterogeneous‡ 1:1 CHCl₃/Cyclohexane 88.4 Heterogeneous‡ 1:1CHCl₃/Cyclohexane 95.7^(a) Heterogeneous† AcOEt 87.7 Heterogeneous†AcOEt 94.8^(a) Homogeneous# MeOH 88.2 Homogeneous# MeOH 96.1^(b)*substrate/ruthenium = 30-100; H₂ pressure = 1350-1450 psig; reactiontemp. = 24° C.; stirring speed = 350 rpm ‡catalyst activation withmethod (B) †in-situ catalysts activation with method (A) #Wan et al., J.Catal. 148, 1 (1994) ^(a)reaction temperature = 3° C. ^(b)reactiontemperature = 3° C. in Wan et al., J. Catal. 148, 1 (1994)

4. Asymmetric Hydrogenation Using Glycerol As The Supported Phase

In the above example, we described an asymmetric reaction on a substratecontaining a prochiral unsaturated carbon-carbon bond. Asymmetricreactions on subtrates containing prochiral unsaturated carbon-heteroatom bonds can also be performed using the supported phase system ofExample 3, for example, the hydrogenation of ketones, imines andbeta-keto esters. These same reactions can be performed as effectivelywith glycerol substitued for ethylene glycol as the support phase, withthe added benefit of glycerol being a much safer and easier to usesolvent than ethylene glycol.

In this example, we describe the asymmetric hydrogenation of ethylbutyrylacetate to the corresponding chiral beta-hydroxy carboxylic esterusing a supported phase catalyst system wherein the supported phase isglycerol. The catalyst system of this example, as shown in the Figure,includes a ruthenium organometallic complex dissolved in a film or layerof glycerol which is supported on a high-surface-area hydrophilic solidparticle, e.g. controlled pore glass (CPG). The Figure shows the use ofglycerol as the support phase for an organometallic catalyst such assulfonated BINAP. (The glycerol is “supported” by the CPG, and“supports” the organometallic catalyst dissolved therein.)

The materials used in this example were as follows: controlled poreglass CPG-240 (a narrow pore-size distribution glass: mean porediameter=242 Å, pore volume=0.89 ml/g, surface area=79 m²/g, meshsize=120/200), benzeneruthenium (II) chloride dimer, ethyl acetate,cyclohexane, chloroform, glycerol and triethylamine in their highestpurity available. The sodium salt of tetra-sulfonated BINAP was preparedas above (Example 1) and all manipulations were performed under argon ornitrogen. Deionized water, distilled over potassium permanganate wasused in all operations requiring water. All solvents, including water,were degassed by four to five freeze-pump-thaw cycles.

The catalyst was prepared and activated in the following manner. Theactive organometallic ruthenium catalyst,[Ru(BINAP-4SO₃Na)(benzene)Cl]Cl, was prepared as above (Example 3) andimpregnated onto the CPG support. The water content of this “dried”catalyst was estimated by thermogravimetric analysis to be 1.9 wt %,while the ruthenium contents were 0.5-1.0×10⁻⁴ mol/g. Anhydrous glycerolwas used to activate the “dried” catalyst in-situ (glycerol partitionsbetween the bulk phase organic solvent and the surface of the CPG) asfollows: 200 mg of the “dried” catalyst in 50-60 μl of anhydrousglycerol was added to 210 mg of ethyl butyrylacetate dissolved in 5 mlof bulk organic phase. The bulk organic phase consisted of a 9:1 mixtureof cyclohexane/ethyl acetate saturated with glycerol.

Asymmetric hydrogenations of ethyl butyrlacetate were conducted at 85°C. in a 25 ml stainless steel Parr batch reactor. Special care was takento avoid introducing oxygen into the reaction mixture at all times. Thehydrogenation reaction was measured by ¹H NMR spectroscopy and theenantiomeric excess (e.e.) determined by HPLC. Complete conversions werefound after stirring at 85° C. for 24 hours. Beta-hydroxy carboxylicesters were formed at 93.4% e.e. (S).

These results compared favorably with the use of ethylene glycol as thesupport phase. The same reaction conditions, with ethylene glycolsubstituted for glycerol, yielded complete conversions at 24 hours withbeta-hydroxy carboxylic esters formed at 95.0% e.e. (S). Thus, glycerolis as effective as a support phase, with the added advantage thatglycerol is much safer to use as a support phase due its lower toxicity.

Thus, alcohol containing solvents, i.e. alcohols having two or morehydroxy groups (diols and triols), have been shown to be useful as thesupported phase for solubilizing the organometallic catalysts of theinvention.

While the present invention is disclosed by reference to the preferredembodiments and examples detailed above, it is to be understood thatthese examples are intended in an illustrative rather than limitingsense, as it is contemplated that modifications will readily occur tothose skilled in the art, which modifications will be within the spiritof the invention and the scope of the appended claims. For example,those skilled in the art will appreciate that the supported phase of theinvention can be another solvent in which the organometallic catalystcan be dissolved but which will not substantially dissolve in the bulkorganic phase.

What is claimed is:
 1. A method for conducting an asymmetric reaction toa prochiral unsaturated bond contained within a compound comprising thestep of contacting said compound with a supported liquid phase catalystcomprising an organometallic compound which comprises a metal and achiral sulfonated 2,2′-bis(diphenylphosphino)-1,1′-binaphthylsolubilized in a solvent having at least two alcohol groups, whereineach phenyl group of the 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl isat least monosulfonated, and wherein the degree to which the2,2′-bis(diphenylphosphino)-1,1′-binaphthyl is sulfonated is selectedfrom the group consisting of tetrasulfonated, pentasulfonated, andhexasulfonated.
 2. A method according to claim 1 wherein the asymmetricreaction is selected from the group consisting of hydrogenation,hydroboration, hydrosilylation, hydride reduction, hydroformylation,alkylation, allylic alkylation, arylation, alkenylation, epoxidation,hydrocyanation, cyclization and disilylation.
 3. A method according toclaim 2 wherein the asymmetric reaction is hydrogenation.
 4. A methodaccording to claim 1 wherein said solvent is ethylene glycol.
 5. Amethod according to claim 1 wherein said solvent is glycerol.
 6. Amethod according to claim 3 wherein said prochiral unsaturated bond is aprochiral unsaturated carbon-hetero atom bond.
 7. A method according toclaim 6 wherein said prochiral unsaturated carbon-hetero atom bondcomprises a prochiral ketone group.
 8. A method according to claim 6wherein said prochiral unsaturated carbon-hetero atom bond comprises aprochiral imine group.
 9. A method according to claim 6, wherein saidcompound is a prochiral beta-keto ester.
 10. A method according to claim9, wherein said beta-keto ester is ethyl butyrylacetate.